Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis.

OBJECTIVES: To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials. DESIGN: Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial. SETTING: Forty community or academic medical institutions in United States and Canada. PATIENTS: One hundred thirty-one adult patients with severe sepsis. INTERVENTIONS: Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs. MEASUREMENTS AND MAIN RESULTS: No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p >.999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p =.021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients. CONCLUSIONS: rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 microg/kg/hr for 96 hrs was selected for use in future clinical studies.

Nicardipine versus nitroprusside for breakthrough hypertension following carotid endarterectomy.

STUDY OBJECTIVE: To evaluate the effectiveness of nicardipine and nitroprusside for breakthrough hypertension following carotid endarterectomy. DESIGN: Prospective, randomized, double-blind, controlled effectiveness trial. SETTING: University-based surgical intensive care unit. PATIENTS: 60 ASA physical status I, II, III, and IV patients experiencing breakthrough hypertension at the time of admission to the intensive care unit (ICU). INTERVENTIONS: Patients received either nicardipine (n = 29) and placebo or nitroprusside (n = 31) and placebo for up to 6 hours postoperatively. Loading doses of nicardipine were provided, but placebo was used as a load for patients randomized to nitroprusside. MEASUREMENTS AND MAIN RESULTS: Rapidity and variability of blood pressure (BP) control were assessed. During the first 10 minutes, 83% of nicardipine patients compared to 23% of nitroprusside-treated patients, achieved BP control (p < 0.01). Following initial control, 12 nicardipine- and 24 nitroprusside-treated patients required additional titration of their infusions to maintain blood pressure within the targeted range (p < 0.05). No patient suffered a stroke, myocardial infarction, or was returned to the operating room (OR) for bleeding. CONCLUSIONS: Nicardipine administration produced more rapid BP control, most likely related to the administration of a loading dose. In addition to more rapid control, nicardipine-treated patients had less variability in BP and required significantly fewer additional interventions. Although no patient suffered a major event during this study, this study was not powered sufficiently to assess safety.

Leukocytes can enhance platelet-mediated aggregation and thromboxane release via interaction of P-selectin glycoprotein ligand 1 with P-selectin.

BACKGROUND: Platelet--leukocyte conjugates have been observed in patients with unstable coronary syndromes and after cardiopulmonary bypass. In vitro, the binding of platelet P-selectin to leukocyte P-selectin glycoprotein ligand-1 (PSGL1) mediates conjugate formation; however, the hemostatic implications of these cell--cell interactions are unknown. The aims of this study were to determine the ability of leukocytes to modulate platelet agonist--induced aggregation and secretion in the blood milieu, and to investigate the role of P-selectin and PSGL-1 in mediating these responses. METHODS: Blood was drawn from healthy volunteers for in vitro analysis of platelet agonist--induced aggregation, secretion (adenosine triphosphate, beta-thromboglobulin, and thromboxane), and platelet-leukocyte conjugate formation. Experiments were performed on live cells in whole blood or plasma to simulate physiologic conditions. Whole-blood impedance and optical aggregometry, flow cytometry, and enzyme-linked immunosorbent assays were performed in the presence and absence of blocking antibodies to P-selectin and PSGL1. The platelet-specific agonists, thrombin receptor activating peptide and adenosine diphosphate, were used to elicit platelet activation responses. RESULTS: Inhibition of platelet--leukocyte adherence by P- selectin and PSGL1 antibodies decreased agonist--induced aggregation in whole blood. The presence of leukocytes in platelet-rich plasma increased aggregation, and this increase was attenuated by P-selectin blocking antibodies. Data from flow cytometry confirmed that platelet-leukocyte conjugate formation contributed to aggregation responses. Blocking antibodies reduced platelet agonist--induced thromboxane release but had no impact on adenosine triphosphate and beta-thomboglobulin secretion. CONCLUSIONS: Leukocytes can enhance platelet agonist--induced aggregation and thromboxane release in whole blood and platelet-rich plasma under shear conditions in vitro. Interaction of platelet P-selectin with leukocyte PSGL1 contributes substantially to these effects.

Bundle-branch block as a risk factor in noncardiac surgery.

BACKGROUND: Despite extensive data examining perioperative risk in patients with coronary artery disease, little attention has been devoted to the implications of conduction system abnormalities. OBJECTIVE: To define the clinical significance of bundle-branch block (BBB) as a perioperative risk factor. METHODS: Retrospective, cohort-controlled study of all noncardiac, nonophthalmologic, adult patients with BBB seen in our preoperative evaluation center. Medical charts were reviewed for data regarding cardiovascular disease, surgical procedure, type of anesthesia, intravascular monitoring, and perioperative complications. RESULTS: Bundle-branch block was present in 455 patients. Right BBB (RBBB) was more common than left BBB (LBBB) (73.8% vs 26.2%). Three patients with LBBB and 1 patient with RBBB died; 1 patient had a supraventricular tachyarrhythmia. Three of the 4 deaths were sepsis related. There were 2 (0.4%) deaths in the control group. There was no difference in mortality between BBB and control groups (P = .32). Subgroup analysis suggested an increased risk for death in patients with LBBB vs controls (P = .06; odds ratio, 6.0; 95% confidence interval, 1.2-100.0) and vs RBBB (P = .06; odds ratio, 8.7; 95% confidence interval, 1.2-100.0). CONCLUSIONS: The presence of BBB is not associated with a high incidence of postoperative cardiac complications. Perioperative mortality is not increased in patients with RBBB and not directly attributable to cardiac complications in patients with LBBB. These data suggest that the presence of BBB does not significantly increase the likelihood of cardiac complications following surgery, but that patients with LBBB may not tolerate the stress of perioperative noncardiac complications.

Intensive care unit telemedicine: alternate paradigm for providing continuous intensivist care.

OBJECTIVE: Intensive care units (ICUs) account for an increasing percentage of hospital admissions and resource consumption. Adverse events are common in ICU patients and contribute to high mortality rates and costs. Although evidence demonstrates reduced complications and mortality when intensivists manage ICU patients, a dramatic national shortage of these specialists precludes most hospitals from implementing an around-the-clock, on-site intensivist care model. Alternate strategies are needed to bring expertise and proactive, continuous care to the critically ill. We evaluated the feasibility of using telemedicine as a means of achieving 24-hr intensivist oversight and improved clinical outcomes. DESIGN: Observational time series triple cohort study. SETTING: A ten-bed surgical ICU in an academic-affiliated community hospital. PATIENTS: All patients whose entire ICU stay occurred within the study periods. INTERVENTIONS: A 16-wk program of continuous intensivist oversight was instituted in a surgical ICU, where before the intervention, intensivist consultation was available but there were no on-site intensivists. Intensivists provided management during the intervention using remote monitoring methodologies (video conferencing and computer-based data transmission) to obtain clinical information and to communicate with on-site personnel. To assess the benefit of the remote management program, clinical and economic performance during the intervention were compared with two 16-wk periods within the year before the intervention. MEASUREMENTS AND MAIN RESULTS: ICU and hospital mortality (observed and Acute Physiology and Chronic Health Evaluation III, severity-adjusted), ICU complications, ICU and hospital length-of-stay, and ICU and hospital costs were measured during the 3 study periods. Severity-adjusted ICU mortality decreased during the intervention period by 68% and 46%, compared with baseline periods one and two, respectively. Severity-adjusted hospital mortality decreased by 33% and 30%, and the incidence of ICU complications was decreased by 44% and 50%. ICU length of stay decreased by 34% and 30%, and ICU costs decreased by 33% and 36%, respectively. The cost savings were associated with a lower incidence of complications. CONCLUSIONS: Technology-enabled remote care can be used to provide continuous ICU patient management and to achieve improved clinical and economic outcomes. This intervention's success suggests that remote care programs may provide a means of improving quality of care and reducing costs when on-site intensivist coverage is not available.

Organizational characteristics of intensive care units related to outcomes of abdominal aortic surgery.

CONTEXT: Morbidity and mortality rates in intensive care units (ICUs) vary widely among institutions, but whether ICU structure and care processes affect these outcomes is unknown. OBJECTIVE: To determine whether organizational characteristics of ICUs are related to clinical and economic outcomes for abdominal aortic surgery patients who typically receive care in an ICU. DESIGN: Observational study, with patient data collected retrospectively and ICU data collected prospectively. SETTING: All Maryland hospitals that performed abdominal aortic surgery from 1994 to 1996. PATIENTS AND PARTICIPANTS: We analyzed hospital discharge data for patients in non-federal acute care hospitals in Maryland who had a principal procedure code for abdominal aortic surgery from January 1994 through December 1996 (n = 2987). We obtained information about ICU organizational characteristics by surveying ICU medical directors at the 46 Maryland hospitals that performed abdominal aortic surgery. Thirty-nine (85%) of the ICU directors completed this survey. MAIN OUTCOME MEASURES: In-hospital mortality and hospital and ICU length of stay. RESULTS: For patients undergoing abdominal aortic surgery, in-hospital mortality varied among hospitals from 0% to 66%. In multivariate analysis adjusted for patient demographics, comorbid disease, severity of illness, hospital and surgeon volume, and hospital characteristics, not having daily rounds by an ICU physician was associated with a 3-fold increase in in-hospital mortality (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.9-4.9). Furthermore, not having daily rounds by an ICU physician was associated with an increased risk of cardiac arrest (OR, 2.9; 95% CI, 1.2-7.0), acute renal failure (OR, 2.2; 95% CI, 1.3-3.9), septicemia (OR, 1.8; 95% CI, 1.2-2.6), platelet transfusion (OR, 6.4; 95% CI, 3.2-12.4), and reintubation (OR, 2.0; 95% CI, 1.0-4.1). Not having daily rounds by an ICU physician, having an ICU nurse-patient ratio of less than 1:2, not having monthly review of morbidity and mortality, and extubating patients in the operating room were associated with increased resource use. CONCLUSIONS: Organizational characteristics of ICUs are related to differences among hospitals in outcomes of abdominal aortic surgery. Clinicians and hospital leaders should consider the potential impact of ICU organizational characteristics on outcomes of patients having high-risk operations.

Beta-adrenergic blockade accelerates conversion of postoperative supraventricular tachyarrhythmias.

BACKGROUND: Postoperative supraventricular tachyarrhythmia is a common complication of surgery. Because chemical cardioversion is often ineffective, ventricular rate control remains a principal goal of therapy. The authors hypothesized that patients with supraventricular tachyarrhythmia after major noncardiac surgery who receive intravenous beta-adrenergic blockade for ventricular rate control would experience conversion to sinus rhythm at a rate that differs from those receiving intravenous calcium channel blockade. METHODS: The rate of conversion to sinus rhythm at 2 and 12 h after treatment was examined in 64 cases of postoperative supraventricular tachyarrhythmia. After adenosine administration, patients who remained in supraventricular tachyarrhythmia were prospectively randomized to receive either intravenous diltiazem or intravenous esmolol for ventricular rate control (unblinded). Loading and infusion rates were adjusted to achieve equivalent degrees of ventricular rate control. RESULTS: Patients were similar with regard to age and Apache III score. Most patients in both groups had atrial fibrillation (esmolol, 79%; diltiazem, 81%), and none experienced stable conversion with adenosine. Patients randomized to receive esmolol experienced a 59% rate of conversion to sinus rhythm within 2 h of treatment, compared with only 33% for patients randomized to receive diltiazem (intention to treat, P = 0.049; odds ratio, 2.9; 95% confidence interval, 1.046 to 7.8). After 12 h of therapy, the number of patients converting to sinus rhythm increased in both groups (esmolol, 85%; diltiazem, 62%), and the rates of conversion no longer differed significantly. Ventricular rates when supraventricular tachyarrhythmia began and after 2 and 12 h of rate control therapy were similar in the two treatment groups. The in-hospital mortality rate and length of stay in the intensive care unit were not significantly influenced by treatment group. CONCLUSIONS: Among adenosine-resistant patients in the intensive care unit with atrial fibrillation after noncardiac surgery, intravenous esmolol produced a more rapid (2-h) conversion to sinus rhythm than did intravenous diltiazem.

Radial artery pressure monitoring underestimates central arterial pressure during vasopressor therapy in critically ill surgical patients.

OBJECTIVES: Radial artery pressure is known to differ from central arterial pressure in normal patients (distal pulse amplification) and in the early postcardiopulmonary bypass period. The adequacy of the radial artery as a site for blood pressure monitoring in critically ill patients receiving high-dose vasopressors has not been carefully examined. DESIGN: Prospective observational study comparing simultaneous intra-arterial measurements of radial (peripheral) and femoral artery (central) pressures. SETTING: Clinical investigation in a university-based surgical intensive care unit. PATIENTS: Fourteen critically ill patients with presumed sepsis who received norepinephrine infusions at a rate of > or =5 microg/min. INTERVENTIONS: All patients were managed in accordance with our standard practice for presumed sepsis, which consisted of intravascular volume repletion followed by vasopressor administration titrated to a mean arterial pressure of > or =60 mm Hg. MEASUREMENTS AND MAIN RESULTS: Systolic and mean arterial pressures were significantly higher when measured from the femoral vs. radial site (p < .005). The higher mean arterial pressures enabled an immediate reduction in norepinephrine infusions in 11 of the 14 patients. No change in cardiac output or pulmonary artery occlusion pressure was noted after dose reduction. In the two patients in whom simultaneous recordings were made after discontinuation of norepinephrine infusions, equalization of mean arterial pressures was observed. CONCLUSIONS: Radial artery pressure underestimates central pressure in hypotensive septic patients receiving high-dose vasopressor therapy. Clinical management, based on radial pressures, may lead to excessive vasopressor administration. Awareness of this phenomena may help minimize adverse effects of these potent agents by enabling dosage reduction.

In vitro hypothermia enhances platelet GPIIb-IIIa activation and P-selectin expression.

BACKGROUND: A clinical bleeding diathesis is associated with hypothermia. Inhibition of platelet reactivity is the purported cause of this coagulopathy despite inconsistent evidence to support this hypothesis. To clarify the effect of temperature on intrinsic platelet function, platelet GPllb-IIIa activation and P-selectin expression were assessed under normothermic and hypothermic conditions in vitro. METHODS: Blood was obtained by venipuncture from healthy volunteers. Platelet activation was assessed by aggregometry and by cytometric analysis of platelet binding of fibrinogen, PAC-1, and P-selectin antibodies. Measurements were made at normothermia (37 degrees C), moderate hypothermia (33 degrees C), and profound hypothermia (22 degrees C) after stimulating samples with adenosine diphosphate (ADP), collagen, or thrombin receptor activating peptide. RESULTS: Agonist-induced platelet aggregation and fibrinogen binding were significantly greater at 22 degrees C and 33 degrees C than at 37 degrees C. Platelet fibrinogen binding values to 20 micro M ADP were 23,400, 14,300, and 9,700 molecules/platelet at 22 degrees C, 33 degrees C, and 37 degrees C, respectively. The aggregation responses of platelets that were cooled and rewarmed were indistinguishable from those of platelets maintained at 37 degrees C throughout the study. Platelet binding of PAC-1 and P-selectin antibodies was greater under hypothermic conditions. CONCLUSIONS: Aggregation, fibrinogen binding, PAC-1 binding, and P-selectin antibody binding studies showed that platelet GPIIb-IIIa activation and alpha-granule release were enhanced at hypothermic temperatures. Thus hypothermia appears to increase the ability of platelets to respond to activating stimuli. The coagulopathy associated with hypothermia is not likely to be the result of an intrinsic defect in platelet function.

Neuroendocrine stress hormones do not recreate the postoperative hypercoagulable state.

UNLABELLED: Surgery causes changes in hemostasis, leading to a hypercoagulable state that has been linked to both arterial and venous thrombotic complications. The etiology of this state is unknown, but many investigators have hypothesized that perioperative neuroendocrine changes are responsible. We have previously demonstrated minimal increases in hemostatic function with a stress hormone infusion. This study was undertaken to further examine the relationship between neuroendocrine hormones and hemostatic function. Seventeen healthy volunteers were administered a stress hormone cocktail i.v. (epinephrine, cortisol, glucagon, angiotensin II, and vasopressin) for 24 h in a blind, placebo-controlled, cross-over design in our clinical research center. Venous blood samples were obtained for measurement of hemostatic function before the infusion and at 2, 8, and 24 h. There were no demonstrable increases in any measure of hypercoagulability. Alternatively, there was an increase in tissue plasminogen activator and protein C activity. These changes are consistent with an inhibition of coagulation and improved fibrinolysis. These data suggest that this combination of neuroendocrine hormones is not responsible for the postoperative hypercoagulable state. IMPLICATIONS: Infusion of five stress hormones (epinephrine, cortisol, glucagon, vasopressin, and angiotensin II) to normal volunteers does not cause increases in procoagulant proteins and platelet reactivity or decreases in fibrinolytic proteins. Alternatively, these five hormones caused increased levels of fibrinolytic proteins (tissue plasminogen activator) and endogenous anticoagulants (protein C antigen and activity).

Postoperative myocardial ischemic events.

During the last 15 years, improved intraoperative hemodynamic management has helped reduce the incidence of myocardial ischemic events, and most events now occur outside the operating room in the first 72 hours following surgery. Currently, what is considered cost-effective management monitors high risk patients in the intensive care unit postoperatively, before transferring them to an unmonitored nursing unit. However, in both monitored and unmonitored areas ischemia is usually not appreciated unless clinical symptoms are present. Thus, our current system of delivering postoperative care is both inefficient and costly. It is clear that we are on the verge of a new frontier in our ability to detect and diagnose perioperative myocardial ischemic events. The possibility of acute real-time intervention and accurate risk stratification using surgery as a stress test is exciting. The challenge at hand is to utilize these modalities in the most beneficial, cost-effective manner. Only through continued quality research can this goal be attained.

Effects of clonidine on prolonged postoperative sympathetic response.

OBJECTIVE: Surgical trauma results in diffuse sympathoadrenal activation which is thought to contribute to perioperative cardiovascular complications in high-risk patients. Regional anesthetic and analgesic techniques can attenuate this "stress response" and reduce the occurrence rate of adverse perioperative events; however, their use in the postoperative period is logistically difficult and costly. The present study was undertaken to evaluate whether transdermal administration of the alpha2 adrenergic-receptor agonist, clonidine, can be used as a pharmacologic means of blunting the stress response throughout the perioperative period. DESIGN: Double-blind, placebo-controlled clinical trial in patients undergoing pancreatico-biliary surgery. SETTING: Operating rooms and surgical intensive care unit of a major university teaching hospital. PATIENTS: Forty patients scheduled for major upper abdominal surgery. INTERVENTIONS: Patients received either clonidine (0.2 mg orally and a clonidine TTS-3 patch the evening before surgery and 0.3 mg orally on call to the operating room) or matched oral and transdermal placebo. MEASUREMENTS AND MAIN RESULTS: Heart rate, systemic arterial blood pressure, plasma catecholamine, clonidine, interleukin-6 concentrations, and 24-hr urine cortisol and nitrogen excretion were measured the day before surgery and daily thereafter for 72 hrs postoperatively. Preoperative transdermal (and oral) clonidine administration resulted in therapeutic plasma clonidine concentrations throughout the perioperative period (1.54 +/- .07 [SEM] microg/mL). Clonidine reduced preoperative epinephrine and norepinephrine concentrations by 65%. Plasma catecholamine concentrations increased in both groups following surgery but were markedly lower throughout the postoperative period in patients receiving clonidine. Patients receiving clonidine had a reduced frequency rate of postoperative hypertension. Clonidine had no effect on plasma interleukin-6 concentration, urine cortisol excretion, or urine nitrogen excretion. No adverse effects of clonidine administration were observed. CONCLUSIONS: The combined administration of oral and transdermal clonidine effectively attenuated the catecholamine response to surgical stress throughout the postoperative study period. Clonidine administration produced specific sympatholytic effects, since other elements of the stress response were not attenuated. Undesirable side effects were not noted. The sustained sympatholytic effects we observed suggest that alpha2 adrenergic-receptor agonists may offer a pharmacologic means of modifying the sympathoadrenal response to injury, and may be useful in reducing perioperative complications.

Effects of storage time on quantitative and qualitative platelet function after transfusion.

BACKGROUND: Platelet transfusions are being used increasingly in patients with thrombocytopenia to improve hemostatic function before surgery and invasive procedures. However, there are limited data on the immediate quantitative and qualitative platelet response after transfusion. Some authors have suggested that transfused platelets require time in vivo to regain maximal function, which is dependent on the duration of platelet storage. Therefore, the timing of surgery and invasive procedures with optimal platelet function may not be occurring. METHODS: Twenty-five patients with thrombocytopenia from ablation chemotherapy and total body irradiation (before bone marrow transplantation), were randomized to receive either 1-day (fresh) or 4-day stored platelets. No patient had infection, organ system dysfunction, or previous platelet transfusion. Single-donor platelets were transfused (1 unit/10 kg body weight) over 60 min. Whole blood from an indwelling central venous catheter was obtained before, immediately after, and 1, 2, and 24 h after transfusion. Platelet number was measured on a Coulter counter and platelet reactivity was measured on a Coulter counter and platelet reactivity was measured using agonist-induced whole blood impedance aggregometry (ohms) and dense granule release (adenosine triphosphate [ATP]). RESULTS: Platelet number increased similarly (21,000 +/- 2,000/mm3 to 76,000 +/- 7,000/MM3 AND 20,000 +/- 1,000/MM3 TO 65,000 +/- 4,000/MM3) after transfusion in the 1- and 4-day stored platelets, respectively. These levels were maintained for 2 h after transfusion in both groups and then decreased similarly (26% and 27%) at 24 h. Agonist-induced platelet aggregation increased immediately after transfusion to 5 micrograms/ml collagen (0.7 +/- 0.4 to 11.4 +/- 1.0 ohms and 0.1 +/- 0.1 to 5.2 +/- 1.0 ohms), 10 micrograms/ml collagen, (1.5 +/- 0.7 to 18.0 +/- 1.9 ohms and 0.6 +/- 0.4 to 10.0 +/- 1.6 ohms) and ristocetin (0.7 +/- 0.4 to 10.1 +/- 1.7 and 0.1 +/- 0.7 to 6.2 +/- 1.0 ohms), in 1- and 4-day, stored platelets, respectively and persisted unchanged in both groups for 2 h. Fresh platelets were hyperaggregable compared to 4-day stored platelets for collagen-induced (5 micrograms/ml and 10 micrograms/ml) aggregation. Agonist-induced platelet dense granule release (ATP) increased immediately after transfusion to 5 micrograms/ml collagen (42 +/- 18 to 410 +/- 49 picomoles ATP and 20 +/- 7 to 186 +/- 22 picomoles ATP), 10 micrograms/ml collagen (60 +/- 22 to 449 +/- 53 picomoles ATP and 44 +/- 13 to 219 +/- 25 picomoles ATP in 1- and 4-day platelets, respectively. Ristocetin-induced ATP release increased immediately after transfusion of fresh platelets only (0 +/- 0 to 69 +/- 17) and remained unchanged for 2 h. Fresh platelets also demonstrated greater dense granule release to collagen (5 micrograms and 10 micrograms/ml) and ristocetin than 4-day stored platelets. CONCLUSIONS: In patients with chemotherapy-induced thrombocytopenia, platelet transfusion causes an immediate increase in number and function, which is independent of storage time. This quantitative and qualitative increase persists unchanged for 2 h after transfusion, suggesting that there is no acute "warm-up-time" necessary for transfused platelets to regain maximal function. Fresh platelets demonstrate increased aggregation and dense granule release compared to 4-day stored platelets and may impart improved hemostatic function in vivo.

Catecholamine and cortisol responses to lower extremity revascularization: correlation with outcome variables. Perioperative Ischemia Randomized Anesthesia Trial Study Group.

OBJECTIVE: To determine whether catecholamine and cortisol secretory responses to surgery contribute to postoperative complications. DESIGN: Prospective, randomized, case series. SETTING: A university hospital operating suite and surgical intensive care unit. PATIENTS: Sixty patients undergoing lower extremity vascular surgery. INTERVENTIONS: Patients were randomized to receive either epidural anesthesia/epidural opiate analgesia (regional anesthesia) or general anesthesia/intravenous patient-controlled analgesia (general anesthesia). MEASUREMENTS AND MAIN RESULTS: Anesthesia was managed according to a prospectively designed protocol. Hemodynamic parameters and plasma catecholamine concentrations were determined at specific intraoperative and postoperative time points. Intraoperative and postoperative urine samples were collected and analyzed for free cortisol concentrations. Outcomes evaluated were cardiac (nonfatal myocardial infarction and cardiac death) and surgical (graft occlusion). Mean arterial pressure during emergence from anesthesia and in the early postoperative period correlated positively with plasma norepinephrine concentration (p < .01). In addition, plasma catecholamine concentrations were higher in patients with postoperative hypertension. Plasma norepinephrine concentrations at the time of emergence from anesthesia and postoperatively were also higher in patients requiring repeat surgery for graft revision, thrombectomy, or amputation (p < .05). Multivariate analysis indicated that the norepinephrine concentration at the time of emergence, but not type of anesthesia, correlated with reoperation for graft occlusion, suggesting that the previously reported beneficial effect of regional anesthesia may be due to modulation of the stress response. Myocardial infarction or cardiac death occurred in three patients. These patients had markedly increased catecholamine concentrations. CONCLUSIONS: The catecholamine response to lower extremity vascular surgery contributes to the development of postoperative hypertension and may also be important in the development of thrombotic complications.

The influence of anesthetic method on infrainguinal bypass graft patency: a closer look.

Although several studies have demonstrated a reduced incidence of postoperative deep venous thrombosis among patients who receive regional anesthesia, the influence of anesthetic method on early arterial bypass graft patency has not been well studied. The records of 78 consecutive patients undergoing elective femoro-popliteal (FP) or femoro-tibial (FT) bypass grafts, and who were randomized to receive general anesthesia and postoperative patient-controlled intravenous narcotic analgesia (GEN, n = 41), or epidural anesthesia and postoperative continuous epidural analgesia (EPI, n = 37), were retrospectively reviewed. The two groups were evenly matched with respect to demographic characteristics, risk factors, and vascular variables. There was one death in each group, yielding an operative mortality of 2.6 per cent, and leaving 76 patients available for further analysis. Graft occlusion occurred in 11 (14.5%) cases within the first 7 postoperative days, including 9 (22.5%) GEN and 2 (5.6%) EPI patients (P < 0.05). There were two (4.4%) FP occlusions, including two (8.7%) GEN and 0(0%) EPI cases; there were nine FT occlusions, including seven (41.2%) GEN and two (14.3%) EPI cases. Graft occlusion occurred in 11 (17.1%) of the 64 limb salvage cases, including nine (27.3%) GEN and two (6.5%) EPI cases (P < 0.05), and in seven (12.7%) of 55 greater saphenous vein grafts, including six (22.2%) GEN and 1 (3.6%) EPI cases (P < 0.05). By multivariate analysis, FT grafts, preoperative plasminogen activator inhibitor-1 (PAI-1) levels, and GEN were predictive of early graft occlusion (P < 0.05). Furthermore, the levels of circulating PAI-1 were higher 24 hours postoperatively among patients in the GEN group (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemostatic effects of stress hormone infusion.

BACKGROUND: Surgery causes changes in hemostasis, leading to a hypercoagulable state. This postoperative increase in hemostatic function is attenuated in patients receiving regional anesthesia compared with those receiving general anesthesia. Regional anesthesia also decreases the neuroendocrine response to surgery compared with general anesthesia, and this effect is hypothesized to be responsible for the differences in hemostatis. To test the hypothesis that neuroendocrine hormones cause changes in hemostasis, we infused stress hormones into normal volunteers and measured hemostatic function. METHODS: After drug screening, 12 normal volunteers were studied. On two admissions, volunteers randomly received either stress hormone (epinephrine, cortisol, or glucagon) or placebo infusion for 24 h. During infusion, patients remained at bed rest and received controlled meals. Blood was obtained from indwelling venous catheters before infusion and 2, 8, and 24 h after the start of infusion. Blood was analyzed for neuroendocrine hormone concentrations, glucose, complete blood count, coagulation proteins, platelet reactivity, and activity of the fibrinolytic system. RESULTS: In the stress hormone group, concentrations of epinephrine, norepinephrine, cortisol, glucagon, and insulin were increased during the infusion period compared with those in the placebo group. Glucose concentrations and white blood cell counts were increased in the stress hormone group compared with those in the placebo group. Circulating fibrinogen concentrations increased 30% and ex vivo collagen-induced platelet reactivity increased 123% (aggregation) and 103% (dense granule release) in the stress hormone infusion group, whereas there was no change in the placebo group. Fibrinolytic proteins were similar in both groups, demonstrating a decrease in plasminogen activator inhibitor-1 activity at 8 and 24 h (196% in the hormone group vs. 199% in the placebo group). CONCLUSIONS: Infusion of stress hormones to concentrations found during surgery is safely tolerated and causes metabolic changes observed with surgery. Stress hormone infusion increases ex vivo platelet reactivity and fibrinogen concentrations that resemble changes seen postoperatively but does not recreate the postoperative decrease in fibrinolytic activity. Differences in neuroendocrine response between types of anesthesia may explain some postoperative changes in platelet function and acute phase reactivity, but additional uncharacterized factors are responsible for the differences in fibrinolysis.

The effects of bedrest on circadian changes in hemostasis.

Venous stasis occurs when people are at bedrest, because of altered venous flow characteristics. This is commonly believed to be one etiology behind the development of deep venous thrombosis (DVT). The hemostatic effects of bedrest and their possible role in DVT development have not been fully examined. We hypothesized that bedrest would lead to increases in hemostatic function and that these increases could be important in the development of DVT. Twelve non-smoking volunteers were studied during supine positioning for 36 hours. Platelet reactivity and plasma concentrations of fibrinogen, alpha 2-antiplasmin, plasminogen, thromboxane beta 2, plasminogen activator inhibitor-1, tissue plasminogen activator and neuroendocrine hormones (cortisol, epinephrine and norepinephrine) were measured at 8:00 a.m., 10:00 a.m., 4:00 p.m. and 8:00 a.m. Cortisol demonstrated an early morning increase while catecholamines were unchanged throughout. Fibrinogen, alpha 2-antiplasmin, plasminogen and platelet reactivity were no different at any time point. Fibrinolytic proteins changed over time, manifested by decreased PAI-1 antigen and activity levels at 24 h. Based upon the parameters measured, bedrest causes no increase in hemostatic function. In fact, bedrest causes the potential for enhanced fibrinolysis, that differs from that previously reported for normal activity over 24 h. This may represent a protective mechanism to counter the effects of stasis from bedrest.